title: The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury.
abstract: The activation of nuclear factor kappa B (NF-κB) p50/RelA is a key event in ischemic neuronal injury, as well as in brain ischemic tolerance. We tested whether epigenetic mechanisms affecting the acetylation state of RelA might discriminate between neuroprotective and neurotoxic activation of NF-κB during ischemia. NF-κB activation and RelA acetylation were investigated in cortices of mice subjected to preconditioning brain ischemia or lethal middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to preconditioning or lethal oxygen-glucose deprivation (OGD). In mice subjected to MCAO and in cortical neurons exposed to lethal OGD, activated RelA displayed a high level of Lys310 acetylation in spite of reduced total acetylation. Also, acetylated RelA on Lys310 interacted strongly with the CREB-binding protein (CBP). Conversely, RelA activated during preconditioning ischemia appeared deacetylated on Lys310. Overexpressing RelA increased Bim promoter activity and neuronal cell death both induced by lethal OGD, whereas overexpressing the acetylation-resistant RelA-K310R, carrying a mutation from Lys310 to arginine, prevented both responses. Pharmacological manipulation of Lys310 acetylation by the sirtuin 1 activator resveratrol repressed the activity of the Bim promoter and reduced the neuronal cell loss. We conclude that the acetylation of RelA in Lys310 dictates NF-κB-dependent pro-apoptotic responses and represents a suitable target to dissect pathological from neuroprotective NF-κB activation in brain ischemia.
authors.affiliation: Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences & Biotechnologies, School of Medicine, University of Brescia, Istituto Nazionale di Neuroscienze Brescia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lanzillotta
authors.forename: I
authors.initials: I
authors.lastname: Sarnico
authors.forename: R
authors.initials: R
authors.lastname: Ingrassia
authors.forename: F
authors.initials: F
authors.lastname: Boroni
authors.forename: C
authors.initials: C
authors.lastname: Branca
authors.forename: M
authors.initials: M
authors.lastname: Benarese
authors.forename: G
authors.initials: G
authors.lastname: Faraco
authors.forename: F
authors.initials: F
authors.lastname: Blasi
authors.forename: A
authors.initials: A
authors.lastname: Chiarugi
authors.forename: P
authors.initials: P
authors.lastname: Spano
authors.forename: M
authors.initials: M
authors.lastname: Pizzi
mesh_terms: D000107:Acetylation; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D050882:CREB-Binding Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000737:chemistry / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D051996:Transcription Factor RelA; D050882:CREB-Binding Protein; D056564:Sirtuin 1; D008239:Lysine